Macrolides have long been known to be effective for treating infectious diseases in humans, livestock, poultry, and other animals. Early macrolides included 16-membered macrolides such as, e.g., tylosin A:
See, e.g., U.S. Pat. No. 4,920,103 (col. 5, lines 12-38). See also, U.S. Pat. No. 4,820,695 (col. 7, lines 1-32) and EP 0103465B1 (page 5, line 3). Over the years, various tylosin derivatives have been developed with the goal of enhancing antibacterial activity and selectivity.
Tylosin derivatives include, e.g., compounds discussed in U.S. Pat. No. 6,514,946 that correspond in structure to Formula (I):
Here:                R1 and R3 are each methyl, and R2 is hydrogen; R1 and R3 are each hydrogen, and R2 is methyl; or R1, R2, and R3 are each hydrogen; and        R4 and R6 are each methyl, and R5 is hydrogen; R4 and R6 are each hydrogen, and R5 is methyl; or R4, R5, and R6 are each hydrogen.Such compounds include, e.g., 20,23-dipiperidinyl-5-O-mycaminosyl-tylonolide, which has the following structure:        
These compounds, and particularly 20,23-dipiperidinyl-5-O-mycaminosyl-tylonolide, are believed to have pharmacokinetic and pharmacodynamic attributes for safe and effective treatment of, e.g., pasteurellosis, bovine respiratory disease, and swine respiratory disease. A discussion relating to the use of these compounds to treat livestock and poultry diseases is included in U.S. Pat. No. 6,514,946. That discussion is incorporated by reference herein. Applicants are not aware of any stable crystalline form of 20,23-dipiperidinyl-5-O-mycaminosyl-tylonolide being described.
Various approaches for making macrolides have been reported.
In EP 0103465B1, e.g., Debono et al. discuss various process steps for making compounds within their recited genus. These processes include, e.g., the following reduction:
Here, R, R1, R2, R3, and R4 are defined as various substituents. R, in particular, is defined as a nitrogen-containing ring system that has up to 3 unsaturated or saturated rings that are optionally substituted. Debono et al. report that the preferred reducing agent is a cyanoborohydride, and that sodium cyanoborohydride is “the reducing agent of choice.” Debono et al. also state that the solvent for this reaction will normally be an inert polar solvent, such as a C1-C4 alkanol. See page 6, lines 7-14. In a later-filed patent in the same patent family, Debono et al. further discuss reductive amination of various aldehyde compounds (including tylosin) with an amine. Sodium cyanoborohydride and sodium borohydride are cited as suitable reducing agents, and anhydrous methanol is cited as a suitable solvent. See U.S. Pat. No. 4,820,695, col. 7, lines 60-68.
In U.S. Pat. No. 6,664,240, Phan et al. also discuss a reductive amination:
Here, Rp2, R4, R7 and R8 are defined as various substituents. R7 and R8, in particular, are each defined as being independent substituents, or, alternatively, as together forming a 3- to 7-member heterocyclic ring. Phan et al. discuss conducting this reaction with a borohydride reagent in an alcohol or acetonitrile solvent. Sodium borohydride and sodium cyanoborohydride are listed as example borohydride reagents; and methanol, ethanol, and isopropanol are listed as example alcohol solvents. See, e.g., col. 15, line 64 to col. 16, line 42; and col. 22, lines 41-49.
In EP 0240264B1, Tao et al. also discuss a reductive amination:
Here, R1, R2, R3, and R4 are defined as various substituents. R3 and R4, in particular, are defined as each being independent substituents, or, alternatively, as together forming a heterocyclic ring system having up to 3 optionally substituted rings. Tao et al. report that this reduction may be achieved using formic acid as the reducing agent. Tao et al. further report that the solvent will ordinarily be an inert polar organic solvent. Amyl acetate and acetonitrile are cited as examples of such a solvent. See page 4, line 57 to page 5, line 10. See also, U.S. Pat. No. 4,921,947, col. 3, line 62 to col. 4, line 16.
In EP 0103465B1, Debono et al. discuss the following hydrolysis reaction:
Here, R, R1, R2, and R4 are defined as various substituents. Debono et al. report that this “hydrolysis can be effected using a strong aqueous mineral acid as hydrochloric or sulfuric acid, or a strong organic acid such as p-toluenesulfonic acid.” See, page 7, lines 3-8. In a later-filed patent of the same patent family, Debono et al. further discuss mycarose hydrolysis of C-20-modified derivatives of tylosin, macrocin, and DOMM using “well known” procedures for acidic hydrolysis. See U.S. Pat. No. 4,820,695, Col. 8, lines 35-43.